1. Field of the Invention
The present invention relates to methods of inhibiting the metallopeptidase, neutral endopeptidase (NEP), which is also referred to as neutral endopeptidase 24.11, CALLA, enkephalinase, enkephalinase A, common acute lymphoblastic leukemia antigen (CALLA) and atriopeptidase. Included are methods for treating acute lymphoblastic leukemia and other CALLA-positive (CALLA+) tumors in mammals, particularly in man. In particular aspects, the invention relates to the identification and selection of NEP inhibitors which are proposed to be useful in treatment of common acute lymphoblastic leukemia, CALLA+ gliomas, certain hepatomas, and hypertension.
2. Description of the Related Art
In mammals, NEP is found in a variety of tissues, including kidney, lung, testes, and brain. Because NEP's biological function can vary from tissue to tissue, it has become known under various names: neutral endopeptidase 24.11, enkephalinase, enkephalinase A, common acute lymphoblastic leukemia antigen (CALLA) and atriopeptidase. Thus the terms NEP, CALLA, and enkephalinase may be used interchangeably to refer to the same protein. NEP is a zinc-containing metallopeptidase. It also is an integral membrane glycoprotein whose structure is thought to be comprised of a twenty amino acid cytoplasmic domain, a single twenty-three amino acid membrane spanning domain, and a 699 amino acid extra-cellular domain, which includes the active site of the enzyme. NEP cleaves peptides on the amino side of hydrophobic amino acids. NEP's known biologically active peptide substrates include Met-Enkephalin, Leu-Enkephalin, ANF, substance P, angiotensin I, II, and III, LHRH, neurotensin, .beta.-lipotropin, oxytocin, fMet-Leu-Phe, neurokinin A, somatostatin, neurokin B, gastrin, bradykinin, gamma-endorphin, Met-Enk-Arg-Phe, CCK-8, Dynorphin-13, Dynorphin-9, Physalaemin, endothelins 1, 2, and 3, and bombesin and its related peptides.
It has been discovered that NEP is identical to an antigen known as common acute lymphoblastic leukemia antigen (CALLA or CD10). CALLA is found on pre B-cell leukemias (49). On mature B-cells CALLA is barely detectable. It is believed that CALLA plays a role in pre B-cell growth and/or differentiation. Through polyclonal and monoclonal antibody techniques, CALLA has been found on the majority of non-T, non-B acute lymphoblastic leukemia cells (48), a large percentage (40%) of chronic myelogenous leukemias in blast crisis (48), on tumor cells from nodular poorly differentiated lymphomas and Burkitt's lymphoma (51) and on myeloma tumor cells (52). The antigen appears absent from acute Myelogenous leukemias and mature B- and T- cell lymphomas (51). CALLA has been detected on early lymphoid progenitor cells and mature granulocyte and fibroblasts (53-55). This antigen has been used in the diagnosis and therapy of lymphoid malignancies (57-59).
The majority of research conducted on NEP has been on its role in pain receptors. The object of such research has been to develop reversible inhibitors as analgesics (see e.g., ref. 34). There is also current interest in reversible NEP inhibitors as antihypertensives. Because of their focus on reversible inhibitors, little effort has been put into finding irreversible inhibitors to NEP. In fact only recently has a mechanism based irreversible inhibitor of a metallopeptidase been published (15).